tbuckley/cabot-search huggingface dataset:
Hydrogel-forming microarray patches with cyclodextrin drug reservoirs for long-acting delivery of poorly soluble cabotegravir sodium for HIV Pre-Exposure Prophylaxis
Authors: Fabiana Volpe-Zanutto, Lalitkumar K. Vora, Ismaiel A. Tekko, Peter E. McKenna, Andi Dian Permana, Akmal H. Sabri, Qonita K. Anjani, Helen O. McCarthy, Alejandro J. Paredes, Ryan F. Donnelly
Journal: Journal of Controlled Release (2022)

Hydrogel-forming microarray patches (HF-MAPs) offer minimally invasive, pain-free and prolonged drug delivery. These devices are designed to be self-administered and self-disabling, avoiding contaminated sharps waste generation. Cabotegravir sodium (CAB-Na) is a poorly soluble anti- human immunodeficiency virus (HIV) drug for the treatment and pre-exposure prophylaxis of HIV infection that lends itself to depot formation following intradermal delivery but presents significant challenges when delivered via HF-MAPs, whose nature is aqueous. Herein, we have investigated, for the first time, the use of hydroxypropyl-β-cyclodextrin (HP-β-CD) to enhance the solubility of CAB-Na, and its effect on intradermal delivery via HF-MAPs. Accordingly, tablet reservoirs containing CAB-Na and HP-β-CD were formulated. These novel reservoirs were combined with two different HF-MAP formulations (MAP1 (Gantrez S97® + poly (ethylene glycol) 10,000 + Na2CO3) and MAP2 (poly (vinyl pyrrolidone) 58 kDa + poly (vinyl alcohol) 85–120 kDa + citric acid)) to form fully integrated MAP devices which were tested in both ex vivo and in vivo settings. Ex vivo skin deposition results for MAP1 and MAP2 showed that 141 ± 40 μg and 342 ± 34 μg of CAB-Na was deposited into 0.5 cm2 of excised neonatal porcine skin after 24 h, respectively. Based on these findings, the in vivo pharmacokinetics of MAP2 were investigated over 28 days using a Sprague-Dawley rat model. After 24 h patch application, MAP2 demonstrated an extended drug release profile and an observed Cmax of 53.4 ± 10.16 μg/mL, superior to that of an FDA-approved CAB-nanosuspension administered via intramuscular application (Cmax of 43.6 ± 5.3 μg/mL). Consequently, this tablet integrated MAP device is considered to be a viable option for the intradermal delivery of hydrophobic anti-HIV drugs.
Brief Report: Exploratory Analysis of Maintenance Therapy in Patients With Extensive-Stage SCLC Treated First Line With Atezolizumab Plus Carboplatin and Etoposide
Authors: Martin Reck, Tony S.K. Mok, Aaron Mansfield, Richard De Boer, Gyorgy Losonczy, Shunichi Sugawara, Rafal Dziadziuszko, Maciej Krzakowski, Alexey Smolin, Maximilian Hochmair, Marina Chiara Garassino, Gilberto de Castro Junior, Helge Bischoff, Sivuonthanh Lam, Andres Cardona, Stefanie Morris, Stephen V. Liu
Journal: Journal of Thoracic Oncology (2022)
PB1775: DEVELOPMENT OF ASSAY CALIBRATION MEHTHODOLOGY FOR CEPHEID XPERT® NPM1 MUTATION PROTOTYPE ASSAY
Authors: Y. Liu, M. Kao, B. Saatian, S. Kayhan, Y. Zhao, A. Aslam, K. Shridhar, L. Yuan
Journal: HemaSphere (2022)

Background: Currently, no International Standards are available for the quantitation of the NPM1 mutation transcript for AML, posing a challenge when developing a quantitative assay to monitor the NPM1 transcript levels. Aims: Implementation of a control material, containing in vitro transcribed RNA (IVT-RNA) of ABL and three major NPM1 subtypes (A, B and D), for standardization of ABL and NPM1 quantifications through copy number (CN) was used to develop an assay calibration methodology at Cepheid. This process generated an in-house control material for assay calibration and standardization of the Xpert NPM1 Mutation Prototype Assay. Methods: A background comparison study was performed by testing contrived clinical samples in EDTA whole blood lysate and PBS lysate to demonstrate the background equivalency for assay performance. Titration studies were performed with Cepheid’s IVT-RNA, containing three subtypes of NPM1 (A, B and D) and ABL, to generate a 6-member control material of A20%, A5%, A1%, A0.2%, B1% and D1% in a PBS lysate background. The NPM1/ABL % value per member was obtained by the IVT-RNA copy number spiked in. A lot-specific curve of delta Ct vs NPM1/ABL % value was generated from the control material for the NPM1 Mutation Prototype Assay, providing an Efficiency Value (E▫▫Ct) and a lot-specific scaling factor (SF). The NPM1/ABL% value of each clinical sample was calculated with E▫▫Ct and SF. A 3-assay comparison study was performed to validate the assay calibration methodology with contrived clinical samples. Results: The background comparison demonstrated the equivalency of assay performance in EDTA whole blood lysate and PBS lysate. The E▫▫Ct and SF of 5 lots of the NPM1 Mutation prototype assay were generated with control material. NPM1/ABL % values of contrived clinical samples in EDTA whole blood from the NPM1 Mutation Prototype Assay were consistent with those from two other comparator assays, RT-ddPCR, and Ipsogen NPM1 MutaQuant assay(Table 1). Image:Summary/Conclusion: Implementing a control material of IVT-RNA allowed linkage of known RNA CN to corresponding Ct, thus providing a methodology to assign an NPM1/ABL % value to any given clinical samples. A lot-specific E▫▫Ct and SF for the NPM1 Mutation Prototype Assay were generated and utilized to calculate the NPM1/ABL % value for a clinical sample. Data from the 3-assay comparison suggested that we established a successful assay calibration methodology with IVT-RNA in PBS lysate background as control material and the NPM1/ABL % value reported by the NPM1 Mutation Prototype Assay was compatible with other comparator assays.
Mechanisms of cellular retention of melanin bound drugs: Experiments and computational modeling
Authors: Sina Bahrpeyma, Mika Reinisalo, Laura Hellinen, Seppo Auriola, Eva M. del Amo, Arto Urtti
Journal: Journal of Controlled Release (2022)

Melanin binding of drugs is known to increase drug concentrations and retention in pigmented eye tissues. Even though the correlation between melanin binding in vitro and exposure to pigmented eye in vivo has been shown, there is a discrepancy between rapid drug release from melanin particles in vitro and the long in vivo retention in the pigmented tissues. We investigated mechanisms and kinetics of pigment-related drug retention experimentally using isolated melanin particles from porcine retinal pigment epithelium and choroid, isolated porcine eye melanosomes, and re-pigmented ARPE-19 cells in a dynamic flow system. The experimental studies were supplemented with kinetic simulations. Affinity and capacity of levofloxacin, terazosin, papaverine, and timolol binding to melanin revealed Kd values of ≈ 50–150 μM and Bmax ≈ 40–112 nmol.mg−1. The drugs were released from melanin in <1 h (timolol) or in 6–12 h (other drugs). The drugs were released slower from the melanosomes than from melanin; the experimental differences ranged from 1.2-fold (papaverine) to 7.4-fold (timolol). Kinetic simulations supported the role of the melanosomal membrane in slowing down the release of melanin binders. In release studies from the pigmented ARPE-19 cells, drugs were released from the cellular melanin to the extracellular space in ≈ 1 day (timolol) and ≈ 11 days (levofloxacin), i.e., much slower than the release from melanin or melanosomes. Simulations of drug release from pigmented cells in the flow system matched the experimental data and enabled further sensitivity analyses. The simulations demonstrated a significant prolongation of drug retention in the cells as a function of decreasing drug permeability in the melanosomal membranes and increasing melanin content in the cells. Overall, we report the impact of cellular factors in prolonging drug retention and release from melanin-containing cells. These data and simulations will facilitate the design of melanin binding drugs with prolonged ocular actions.
Retinal vessel diameters and function in cardiovascular risk and disease
Authors: Henner Hanssen, Lukas Streese, Walthard Vilser
Journal: Progress in Retinal and Eye Research (2022)

In the last two decades evidence has gradually accumulated suggesting that the eye may be a unique window for cardiovascular risk stratification based on the assessment of subclinical damage of retinal microvascular structure and function. This can be facilitated by non-invasive analysis of static retinal vessel diameters and dynamic recording of flicker light-induced and endothelial function-related dilation of both retinal arterioles and venules. Recent new findings have made retinal microvascular biomarkers strong candidates for clinical implementation as reliable risk predictors. Beyond a review of the current evidence and state of research, the article aims to discuss the methodological benefits and pitfalls and to identify research gaps and future directions. Above all, the potential use for screening and treatment monitoring of cardiovascular disease risk are highlighted. The article provides fundamental comprehension of retinal vessel imaging by explaining anatomical and physiological essentials of the retinal microcirculation leading to a detailed description of the methodological approach. This allows for better understanding of the underlying retinal microvascular pathology associated with the prevalence and development of cardiovascular disease. A body of new evidence is presented on the clinical validity and predictive value of retinal vessel diameters and function for incidence cardiovascular disease and outcome. Findings in children indicate the potential for utility in childhood cardiovascular disease prevention, and the efficacy of exercise interventions highlight the treatment sensitivity of retinal microvascular biomarkers. Finally, coming from the availability of normative data, solutions for diagnostic challenges are discussed and conceptual steps towards clinical implementation are put into perspective.
PB1800: DEEPDECON: A DEEP-LEARNING METHOD FOR DETECTING MINIMAL RESIDUAL DISEASE OF ACUTE MYELOID LEUKEMIA
Authors: J. Zhong, A. Stucky, F. Sun, J. Huang
Journal: HemaSphere (2022)

Background: Acute myeloid leukemia (AML) is a heterogeneous disease that the myeloid lineages of hematopoietic progenitor cells (blasts) lose the ability of normal differentiation and build up in the bone marrow. The ability to identify minimal residual disease (MRD) below the morphology-based 5% blast threshold has significant impact in clinical outcome. Flow cytometry and real-time quantitative polymerase chain reaction [qPCR]) are the most common methods for MRD detection while next-generation sequencing (NGS) is emerging as a more sensitive method. Aims: Here, we report DeepDecon, a deep neural network model that utilizes NGS RNAseq data to detect MRD of AML. Methods: DeepDecon makes use of the non-linear transformation among the latent layers and learns to extract high-order representations of the input gene expression. Meanwhile, DeepDecon doesn’t need to select a subset of genes. The neural network will optimize and assign different weights to all genes to minimize the prediction error. A challenging issue with deep learning models is the need for large data sets of diverse examples for model training to obtain robust and good performance. With single-cell RNAseq data, we digitally create a large number of bulk RNAseq samples with known AML fraction for model training. Results: When applied to clinical data TARGET-AML from GDC Data Portal (https://portal.gdc. cancer.gov/), DeepDecon demonstrated better performance than other machine learning algorithms, including MuSic, NNLS, Bisque, RNA-Sieve, and Scaden, for detecting MRD of AML. Summary/Conclusion: Deepdecon can be applied to clinical NGS data for accurate and sensitive detection of MRD in AML treatment. It will significantly improve the clinical outcomes of current AML therapy.
Clinical outcomes of high-risk cutaneous squamous cell carcinomas treated with Mohs surgery alone: An analysis of local recurrence, regional nodal metastases, progression-free survival, and disease-specific death
Authors: Teo Soleymani, David G. Brodland, Julia Arzeno, Danny J. Sharon, John A. Zitelli
Journal: Journal of the American Academy of Dermatology (2022)

The incidence of cutaneous squamous cell carcinoma (cSCC) continues to increase, and it is now predicted that the number of deaths from cSCC will surpass that of melanoma within the next 5 years. Although most cSCCs are successfully treated, there exists an important subset of high-risk tumors that have the highest propensity for local recurrence (LR), nodal metastasis (NM), and disease-specific death (DSD).We investigated the clinical outcomes of high-risk cSCCs treated with Mohs surgery (MS) alone, analyzing LR, NM, distant metastasis, and DSD. In addition, we analyzed progression-free survival and DSD in patients who underwent salvage head/neck dissection for regional NMs.Retrospective review of all high-risk cSCC treated in our clinics between January 1, 2000, and January 1, 2020, with follow-up through April 1, 2020.Two university-affiliated, private-practice MS referral centers.In total, 581 high-risk primary cSCCs were identified in 527 patients, of which follow-up data were obtained for 579 tumors. The 5-year disease-specific survival was 95.7%, with a mean survival time of 18.6 years. The 5-year LR-free survival was 96.9%, the regional NM-free survival was 93.8%, and the distant metastasis-free survival was 97.3%. The 5- and 10-year progression-free survival rates from metastatic disease were 92.6 and 90.0%, respectively. In patients who experienced regional NMs and underwent salvage head and neck dissection with or without radiation, the 2-year disease-specific survival was 90.5%.Our cohort, which is the largest high-risk cSCC cohort treated with MS to date, experienced lower rates of LR, NM, and DSD than those reported with historical reference controls using both the Brigham and Women's Hospital and American Joint Committee on Cancer, Eighth Edition, staging systems. We demonstrated that MS confers a disease-specific survival advantage over historical wide local excision for high-risk tumors. Moreover, by improving local tumor control, MS appears to reduce the frequency of regional metastatic disease and may confer a survival advantage even for patients who develop regional metastases.
Programmed Death-Ligand 1 and Programmed Death-Ligand 2 mRNAs Measured Using Closed-System Quantitative Real-Time Polymerase Chain Reaction Are Associated With Outcome and High Negative Predictive Value in Immunotherapy-Treated NSCLC
Authors: Aileen I. Fernandez, Niki Gavrielatou, Leena McCann, Saba Shafi, Myrto K. Moutafi, Sandra Martinez-Morilla, Ioannis A. Vathiotis, Thazin Nwe Aung, Vesal Yaghoobi, Yalai Bai, Yvonne G. Chan, Jodi Weidler, Roy Herbst, Michael Bates, David L. Rimm
Journal: Journal of Thoracic Oncology (2022)
Exiting the Anthropocene: Achieving personal and planetary health in the 21st century
Authors: Susan L. Prescott, Alan C. Logan, Jamie Bristow, Ricardo Rozzi, Rob Moodie, Nicole Redvers, Tari Haahtela, Sara Warber, Blake Poland, Trevor Hancock, Brian Berman
Journal: Allergy (2022)

Planetary health provides a perspective of ecological interdependence that connects the health and vitality of individuals, communities, and Earth's natural systems. It includes the social, political, and economic ecosystems that influence both individuals and whole societies. In an era of interconnected grand challenges threatening health of all systems at all scales, planetary health provides a framework for cross-sectoral collaboration and unified systems approaches to solutions. The field of allergy is at the forefront of these efforts. Allergic conditions are a sentinel measure of environmental impact on human health in early life-illuminating how ecological changes affect immune development and predispose to a wider range of inflammatory noncommunicable diseases (NCDs). This shows how adverse macroscale ecology in the Anthropocene penetrates to the molecular level of personal and microscale ecology, including the microbial systems at the foundations of all ecosystems. It provides the basis for more integrated efforts to address widespread environmental degradation and adverse effects of maladaptive urbanization, food systems, lifestyle behaviors, and socioeconomic disadvantage. Nature-based solutions and efforts to improve nature-relatedness are crucial for restoring symbiosis, balance, and mutualism in every sense, recognizing that both personal lifestyle choices and collective structural actions are needed in tandem. Ultimately, meaningful ecological approaches will depend on placing greater emphasis on psychological and cultural dimensions such as mindfulness, values, and moral wisdom to ensure a sustainable and resilient future.
Genomic Profiling of Bronchoalveolar Lavage Fluid in Lung Cancer
Authors: Viswam S. Nair, Angela Bik-Yu Hui, Jacob J. Chabon, Mohammad S. Esfahani, Henning Stehr, Barzin Y. Nabet, Li Zhou, Aadel A. Chaudhuri, Jalen Benson, Kelsey Ayers, Harmeet Bedi, Meghan Ramsey, Ryan Van Wert, Sanja Antic, Natalie Lui, Leah Backhus, Mark Berry, Arthur W. Sung, Pierre P. Massion, Joseph B. Shrager, Ash A. Alizadeh, Maximilian Diehn
Journal: Cancer Research (2022)

Abstract Genomic profiling of bronchoalveolar lavage (BAL) samples may be useful for tumor profiling and diagnosis in the clinic. Here, we compared tumor-derived mutations detected in BAL samples from subjects with non–small cell lung cancer (NSCLC) to those detected in matched plasma samples. Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) was used to genotype DNA purified from BAL, plasma, and tumor samples from patients with NSCLC. The characteristics of cell-free DNA (cfDNA) isolated from BAL fluid were first characterized to optimize the technical approach. Somatic mutations identified in tumor were then compared with those identified in BAL and plasma, and the potential of BAL cfDNA analysis to distinguish lung cancer patients from risk-matched controls was explored. In total, 200 biofluid and tumor samples from 38 cases and 21 controls undergoing BAL for lung cancer evaluation were profiled. More tumor variants were identified in BAL cfDNA than plasma cfDNA in all stages (P &amp;lt; 0.001) and in stage I to II disease only. Four of 21 controls harbored low levels of cancer-associated driver mutations in BAL cfDNA [mean variant allele frequency (VAF) = 0.5%], suggesting the presence of somatic mutations in nonmalignant airway cells. Finally, using a Random Forest model with leave-one-out cross-validation, an exploratory BAL genomic classifier identified lung cancer with 69% sensitivity and 100% specificity in this cohort and detected more cancers than BAL cytology. Detecting tumor-derived mutations by targeted sequencing of BAL cfDNA is technically feasible and appears to be more sensitive than plasma profiling. Further studies are required to define optimal diagnostic applications and clinical utility. Significance: Hybrid-capture, targeted deep sequencing of lung cancer mutational burden in cell-free BAL fluid identifies more tumor-derived mutations with increased allele frequencies compared with plasma cell-free DNA. See related commentary by Rolfo et al., p. 2826
A 3-Fr microcatheter is suitable for a 0.018-inch guidewire during endoscopic ultrasound-guided biliary drainage
Authors: Akihisa Kato, Michihiro Yoshida, Kenta Kachi, Yasuki Hori, Itaru Naitoh, Kazuki Hayashi, Hiromi Kataoka
Journal: Endoscopy (2022)

A combination of a 22-gauge needle and a 0.018-inch guidewire has become popular for patients with an insufficiently dilated bile duct during endoscopic ultrasound-guided biliary drainage (EUS-BD) [1] [2] [3]. However, this combination has several disadvantages, including an insufficient contrast-filled image and limited ability to manipulate the guidewire because of the slimness [1]. Although the catheter must be inserted into the bile duct across the fistula in a challenging situation of this kind, advancing a conventional catheter over a 0.018-inch guidewire can sometimes be difficult because of the gap between the guidewire and the catheter. Here, we report the first use of a new 3-Fr microcatheter that we produced previously [4], which has the following advantages for use with a 0.018-inch guidewire during EUS-BD: (i) it allows easy insertion because of its slimness and flexibility, (ii) it provides a sufficient contrast-filled image, (iii) it assists in manipulating the guidewire to advance into the target space, (iv) it avoids unnecessary dilation until needed, and (v) it allows exchange of the guidewire from 0.018-inch to 0.025-inch to provide support for device insertion ([Fig. 1]).
Erythropoietic effects of vadadustat in patients with anemia associated with chronic kidney disease
Authors: Mark J. Koury, Rajiv Agarwal, Glenn M. Chertow, Kai‐Uwe Eckardt, Steven Fishbane, Tomas Ganz, Volker H. Haase, Mark R. Hanudel, Patrick S. Parfrey, Pablo E. Pergola, Prabir Roy‐Chaudhury, James A. Tumlin, Robert Anders, Youssef M. K. Farag, Wenli Luo, Todd Minga, Christine Solinsky, Dennis L. Vargo, Wolfgang C. Winkelmayer
Journal: American Journal of Hematology (2022)

Abstract Patients with chronic kidney disease (CKD) develop anemia largely because of inappropriately low erythropoietin (EPO) production and insufficient iron available to erythroid precursors. In four phase 3, randomized, open‐label, clinical trials in dialysis‐dependent and non–dialysis‐dependent patients with CKD and anemia, the hypoxia‐inducible factor prolyl hydroxylase inhibitor, vadadustat, was noninferior to the erythropoiesis‐stimulating agent, darbepoetin alfa, in increasing and maintaining target hemoglobin concentrations. In these trials, vadadustat increased the concentrations of serum EPO, the numbers of circulating erythrocytes, and the numbers of circulating reticulocytes. Achieved hemoglobin concentrations were similar in patients treated with either vadadustat or darbepoetin alfa, but compared with patients receiving darbepoetin alfa, those receiving vadadustat had erythrocytes with increased mean corpuscular volume and mean corpuscular hemoglobin, while the red cell distribution width was decreased. Increased serum transferrin concentrations, as measured by total iron‐binding capacity, combined with stable serum iron concentrations, resulted in decreased transferrin saturation in patients randomized to vadadustat compared with patients randomized to darbepoetin alfa. The decreases in transferrin saturation were associated with relatively greater declines in serum hepcidin and ferritin in patients receiving vadadustat compared with those receiving darbepoetin alfa. These results for serum transferrin saturation, hepcidin, ferritin, and erythrocyte indices were consistent with improved iron availability in the patients receiving vadadustat. Thus, overall, vadadustat had beneficial effects on three aspects of erythropoiesis in patients with anemia associated with CKD: increased endogenous EPO production, improved iron availability to erythroid cells, and increased reticulocytes in the circulation.